Summary: The Laboratory Chief was chosen a principle investigator for a $3.8 million contract with DARPA spanning 18 months to determine if a diet of ketone esters can enhance the physical performance in rats by 30% while maintaining cognitive function. Components in this contract were comprised of 3 universities and 3 commercial entities. cognitive performance of war fighters under conditions of extreme physiological and emotional stress. The basis for this hypothesis was contained in previous work from this laboratory which showed that ketone bodies could improve the hydraulic work of the working perfused rat heart by 28% compared to glucose alone [1] and overcome insulin resistance [2;3]. During this project, we: 1) obtained a CE mass spec to increased speed and throughput of our metabolite analyses, 2) developed a new method for the enzymatic synthesis of ketone esters a patent application for which was filed by NIH, 3) produced an improved enzyme for the measurement of ketone bodies in animal fluids and tissues, 4) developed a non-invasive optical method for measurement of tissue ketone levels, 5) demonstrated absorbability of chosen ketone ester from gut with maintenance of therapeutic blood levels for over 6 hours without acute toxicity, 6) improved exercise tolerance in rats 3 fold over rats consuming an equivalent to normal army rations, MRE, and 7) decreased maze running time by ? while doubling the number of correct maze decisions demonstrating improved cognitive performance. We thus exceeded our stated goals defined for this project. Accordingly the Laboratory Chief was appointed as principle investigator for a Phase II contract with DARPA in the amount of $6.8 million over 2 years to: 1) synthesize 500 kg of cGMP ketone esters, 2) formulate a ketone and placebo diet suitable for testing in humans, 3) demonstrate lack of toxicity of these diets, 4) obtain FDA GRAS status for ketone ester diets, 5) obtain IRB approval of testing from Oxford University, NIH and DoD and 6) test the efficacy of the diet to enhance physical and cognitive performance in human subjects under extreme conditions of physical and emotional stress. The production of these test diets is scheduled for testing in human subjects in early 2007. There is no provision in this project for the testing of these diets in a number of diverse disease phenotypes in this DoD project. It is hoped that consideration of the use of these materials in the relevant disease phenotypes [4;5] will be considered and undertaken by the relevant institutes at NIH. SIGNIFICANCE TO THE PROGRAMS OF THE NIAAA Furtherance of defenses against bioterrorism is one of the priorities in the NIH roadmap and this collaboration with the Department of Defense is consonant with this NIH priority. The possibility of developing a new therapy for a presently untreatable diseases is of significance to the mission of the NIH and this institute.